Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

published_or_final_version / abstract / Medicine / Master / Master of Philosophy

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Pharmacology / Master / Master of Philosophy

published_or_final_version / Medicine / Master / Master of Philosophy

published_or_final_version / Pharmacology and Pharmacy / Master / Master of Philosophy

Barrett's esophagus (BE) is a premalignant disease associated with esophageal adenocarcinoma (EAC). This condition is highly associated with gastroesophageal reflux disease (GERD) which is characterized as chronic exposure of the esophagus to acid and bile acids. An understanding of the cytotoxic and tumorigenic capacity of bile acids and acid during a reflux episode will lead to the identification of markers for therapeutic intervention. The major goal of the following studies was to determine the mechanisms responsible for bile acid-induced alteration in intracellular pH (pHi) the effect on DNA damage, apoptosis and the adaptive resistance to reflux episodes in cells derived from normal esophagus (HET1A) or BE (CP-A) and EAC (JH-EsoAd1). In addition, I explored the therapeutic potential of UDCA oral therapy in BE cells.Here we show a novel mechanism of bile acid-induced, nitric oxide-mediated inhibition of the sodium-hydrogen exchanger (NHE) is a pathway bile acids utilize to induce acid-mediated DNA damage. This same mechanism can elicit apoptosis-resistance which we demonstrate by the complete inhibition of NHE with pharmacological inhibitor of NHE, EIPA. In addition, chronic exposure of bile acids and acid, in-vitro, confers resistance to cytotoxicity and makes cells derived from the squamous epithelium of the esophagus resemble BE and EAC. Finally, modifying the bile acid composition with glycol-Ursodeoxycholic acid (GUDCA) prevents many of the malignant effects of bile acids and acid and suggests a possible therapeutic strategy for those that suffer from GERD. The conclusion from this study suggest that bile acid reflux should be controlled in patients who suffer from GERD

Sex dimorphism in the prevalence, onset, development and progression of cardiovascular disease (CVD) is well recognized. Sex-specific differences in adaptation to cardiac pathological progressions such as cardiac hypertrophy (CH), and the extent to which they are attributable to sex hormones requires further delineation. The objective of this dissertation was to determine which cardiac vasoactive systems are responsible for sex-specific differences in CH modulation using the atrial natriuretic peptide gene-disrupted (ANP-/-) mouse model. First, sex-specific differences in the expression of the cardiac natriuretic peptide (NP) and nitric oxide synthase (NOS) systems were evaluated. Next, the influence of 17β-Estradiol (E2) on the expression and signaling of the cardiac NP and NOS systems was determined in ovariectomized (OVX) female ANP+/+ and ANP-/- mice. Finally, sex-specific differences in cardiac adaptation to Angiotensin II (ANGII) pressure overload were elucidated in male and intact female ANP+/+ and ANP-/- mice. These studies revealed that males predominantly use the NP system and females predominantly use the NOS system. Sex-specific differences in the cardiac NOS system were further enhanced by E2 in OVX female ANP+/+ and ANP-/- mice. In the female ANP-/- mouse, E2 was found to signal through the NOS system to significantly increase plasma cGMP. Finally, male and female differences were demonstrated in the sex-specific patterns of cardiac vasoactive gene system expression and development of cardiac dysfunction in response to ANGII treatment. Sex dimorphism was observed in the expression of BNP and NPR-A in male and female ANP-/- mice treated with ANGII. Female ANP+/+ and ANP-/- ANGII-treated mice exhibited elevated E/E’ ratios that were not found to the same extent in genotype matched ANGII-treated male mice, demonstrating that female mice developed ANGII-mediated mild left ventricle diastolic dysfunction. Based on the results of this dissertation, we conclude that sex-specific differences do indeed exist in the cardiac adaptation to pathological stresses. These data support the understanding that a progression towards sex-specific CVD treatments is warranted, with a particular emphasis on the potential benefits of female-specific targeting of the cardiac NOS system. / Thesis (Ph.D, Anatomy & Cell Biology) -- Queen's University, 2013-08-23 14:21:45.324

No description available.

Hypertensive patients exhibit impaired exercise capacity, a strong independent risk factor for cardiovascular disease, and the mechanisms responsible for this are not fully determined. Potential candidates may include endothelial vasomotor dysfunction and arterial stiffness, both of which are associated with hypertension. Impairment of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a major role in the development of these abnormalities, suggesting that enhancement of NO-cGMP signalling through phosphodiesterase type 5 (PDE5) inhibition may offer therapeutic potential in arterial hypertension. This thesis investigated the effects of the PDE5 inhibitor sildenafil citrate on exercise-induced vasodilatation, maximal exercise capacity and arterial stiffness in hypertensive patients, using different studies involving local limb and whole body exercise. Preliminary dose-ranging studies were initially performed to investigate the intraarterial (brachial) effects of sildenafil on forearm blood flow (FBF), and to select an appropriate, cGMP-independent, vasodilator to use as a control. On the basis on these studies, it was established that sildenafil, infused at 50μg/min, and verapamil, infused at 5μg/min, had similar vasodilator effect on FBF. Ten untreated hypertensive patients and ten matched normotensive subjects were then studied in a three-way, randomised, single-blind and placebo-controlled FBF study. The aim was to investigate the effects of sildenafil on handgrip exercise-induced vasodilatation, and to compare this response with verapamil and saline (placebo). Preinfusion exercise-induced vasodilatation was significantly reduced in hypertensive compared with normotensive subjects (P<0.001). However, after the infusions, while verapamil did not affect the vasodilator response to exercise in either group, sildenafil substantially enhanced this response in hypertensive patients, but not in normotensive subjects (P<0.05). These results suggested that sildenafil, through an increase in cGMP levels in the vasculature, substantially and selectively improves the vasodilator response to handgrip exercise in hypertensive patients.